Is CHCHD10 p.Ala92fs (c.274del) pathogenic?

CHCHD10 p.Ala92fs (c.274del) is classified Uncertain significance in CHCHD10 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-11). Very rare (popmax 9.15e-05%, nfe); Associated with lower motor neuron syndrome with late-adult onset.

How common is CHCHD10 p.Ala92fs (c.274del) in the general population?

CHCHD10 p.Ala92fs (c.274del) is very rare (popmax 9.15e-05%, nfe) (gnomAD).

How is Lower motor neuron syndrome with late-adult onset inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHCHD10 p.Ala92fs

Q: What condition is associated with CHCHD10 p.Ala92fs (c.274del)?

CHCHD10 p.Ala92fs (c.274del) is associated with lower motor neuron syndrome with late-adult onset, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, autosomal dominant mitochondrial myopathy with exercise intolerance (ClinVar).

c.274del · rs2517618074 · VCV2952775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 9.15e-05%, nfe)

Conditions

lower motor neuron syndrome with late-adult onset

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.6	GERP 0.2, phastCons 0.65

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.15e-05% European (non-Finnish) · 1/1,092,914 alleles

Overall 0.000135% 2/1,486,376 alleles · very rare exomes 2/1,334,550 · genomes 0/151,826 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00174%	57,580
European (non-Finnish)grpmax	9.15e-05%	1,092,914

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CHCHD10
Protein: p.Ala92fs
Coding: c.274del
MANE Select: NM_213720
dbSNP: rs2517618074
Type: Deletion
Location: chr22:23766263 (GRCh38)
Gene constraint: LOEUF 1.543 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.01 · 5 PDB
Residue 92: the 'disordered' region

Full CHCHD10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lower motor neuron syndrome with late-adult onset — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: frontotemporal dementia and/or amyotrophic lateral sclerosis 2 autosomal dominant mitochondrial myopathy with exercise intolerance

For Lower motor neuron syndrome with late-adult onset (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CHCHD10 p.Ala92Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CHCHD10 p.Ala92Pro Benign/Likely benign ★★ same residue
CHCHD10 p.Gly4fs Uncertain significance ★ same condition
CHCHD10 c.410-8del Likely benign ★ same condition
CHCHD10 c.42-5del Likely benign ★ same condition
CHCHD10 p.Ala92= Likely benign same residue
CHCHD10 p.Ser59Leu Pathogenic/Likely pathogenic ★★ same condition
CHCHD10 c.262-3C>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/chchd10-p-ala92fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown